BACKGROUND Chronic inflammatory arthropathies pose a diagnostic and therapeutic challenge to the treating physician. At the initial presentation, rheumatoid arthritis (RA), spondyloarthropathies, and other undifferentiated arthropathies frequently overlap in their clinical manifestations. The etiology and pathogenesis of these diseases is not well understood and reliable diagnostic and prognostic factors are often insufficient to differentiate disease subsets early in the course of the disease to which appropriate therapeutic strategies could then be applied. The focus of research has centered on the association of genetic susceptibility and infectious triggers and the understanding of the complex interactions between genetic and envionmental factors has allowed some hyposthesis about the pathogenesis of these diseases. Infectious triggers have long been suspected for some forms of arthritis and have been identified in the context of so-called "reactive" arthritis. In the case of rheumatoid arthritis, a number of pathogens have been suspected, and in some studies, clinical and molecular evidence of association has been demonstrated for specific organisms. Studies in a different group of patients with RA have failed to confirm a consisten association with a single pathogen. This has led to the hypothesis that multiple pathogens can potentially serve as either initiators or amplifiers of the inflammatory processes which are centered primarily in the synovial membrane. There a complex interaction between cellular recruitment, proliferation, leads to activation of a pannus of inflamed, proliferactive, tumor like synovium, that invades and destroys the adjacent bone and cartilage, resulting ultimately, also not predictably, and functional loss. We still lack reliable prognostic factors early in the course of inflammatory arthropathies. Although a number of clinical, serologic and immunogenetic factors have been shown to be associated with poor outcome of RA, in the case of spondyloarthropathies and undifferentiated arthropaties, there is less known about determining factors. However, persistent inflammation of the synovial membrane is the most important predictor of a damaging chronic arthropathy. NIH EARLY SYNOVITIS COHORT In an attempt to define pathogeneic mechanisms, identify prognostic factors, as well as look for infectious agents, which may be involved in the etiology and pathogenesis of arthritis, the NIH early synovitis cohort was established in 1994. Patients with synovitis of one or more peripheral joints of less than 12 months duration have been recruited into this protocol. Patients undergo a thorough clinical examination along with a detailed hematological, serological, radiographic and immunogenetic evaluation. All patients undergo a closed synovial needle biopsy at the initial visit. Synovial fluid and tissue are analyzed for the presence of specific genes from pathogen such as Chlamydia trachomatis, using PCR. The synovial tissue biopsies are assessed Histopathologically and immunohistologically. These patients are then reevaluated clinically at six weeks six-month and one year. RESULTS DURING THE PAST YEAR AND ONGOING INITIATIVES A number of initiatives and studies centered around this cohort have either come to fruition over the past year or are ongoing. These include the following: 1. During the last year over 50 new patients have been recruited into the protocol and have undergone a synovial biopsy. Among those 43% fulfilled the ACR critieria for RA, 21% the European Spondylarthopathy Study Group (ESSG) criteria for spondylarthopathy and 36% remained unclassified. 2. Multiple genetic loci seem to be associated with the susceptibility or severity of RA. Continuous evaluation of genetic susceptibility loci have revealed that certain DQ alleles are strongly associated with the diagnosis of RA especially in the absence of a protective motif within several MHC class II alleles (Hoxworth J et al manuscript submitted), certain TNF receptor polymorphism seem to be more frequent in patients with RA than in the general population. Testing of other genes potentially associated with RA are still ongoing, including the CACP gene recently described by Dr. Jeff Trent's group. 3. Several studies focusing on the presence and impact of bacterial triggers in the synovium have been completed. DNA of Parvovirus B19 has been found in a spectrum of patients with early synovitis and is not disease specific (El-Gabalawy et al, in preparation), IgM and IgA antibodies are stongly associated with the presence of RA primarily in RF+RA patients (Goldbach-Mansky et al, in preparation) and work looking for the presence of bacterial peptidoglycans that may be involved in the amplification of inflammatory processes is still ongoing. 4. Granzyme A and B are secreted by cytotoxic T cells and have been proposed to play a role in inflammatory arthropathies. We found that Granzyme B but not Granzyme A levels are highest in patients with RF+RA, and predictive of early erosions in these patients (Goldbach-Mansky et al, in preparation). The role of this enzyme in the generation of antigens that are recognized by RA associated autoantibodies is ongoing. 5. The pathologic assessment of the synovial tissue has been completed on 160 tissue samples. None of the histologic findings are disease specific. However, erosive synovial tissues are associated with a higher degree of lymphocytic infiltrate, lining layer thickness, tissue necrosis and the degree of tissue ischemia. 6. Endothelial abnormalities occur early in the course of disease and allow trafficking of inflammatory cells into the synovial tissue. Evaluation of the endothelium in the synovial tissue samples in patients with early synovitis reveals that there is considerable angiogenesis in these lesions irrespective of diagnosis. 7. Performance measures have been evaluated in the early synovitis cohort by Dr. Lynn Gerber's group. The data suggests that poor performance is predicted by the number of affected joints rather than the underlying diagnosis. Recruitment into this study has been completed in 7/30/00 and data from this study are still being analyzed. SIGNIFICANCE A unique cohort of early synovitis patients have been recruited to the NIH. The strength of this initiative relates to the heterogeneity of the cohort, allowing it to be representative of what clinicians encountered in routine clinical practice. The acquisition of synovial tissue samples from the entire cohort allows the testing of etiologic and pathogenetic hypothesis related to chronic inflammatory arthropathies. It is hoped that this project will allow the generation of a robust model to predict disease outcome, which would incorporate a spectrum of early prognostic features, including clinical disease patterns, genetics, and pathological variables. This model should prove invaluable to clinicians who are attempting to stratify patients for therapeutic strategies, early in their disease course.